EP0374675A2 - Reduction of piperidine-dion-derivatives and intermediates - Google Patents

Reduction of piperidine-dion-derivatives and intermediates Download PDF

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Publication number
EP0374675A2
EP0374675A2 EP89122827A EP89122827A EP0374675A2 EP 0374675 A2 EP0374675 A2 EP 0374675A2 EP 89122827 A EP89122827 A EP 89122827A EP 89122827 A EP89122827 A EP 89122827A EP 0374675 A2 EP0374675 A2 EP 0374675A2
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Prior art keywords
piperidine
trans
prepared
pentyl
same way
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EP89122827A
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German (de)
French (fr)
Inventor
Jane Marie Lundbeck
Svend Treppendahl
Palle Jakobsen
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Novo Nordisk AS
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Ferrosan ApS
Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates to a novel chemical process for pre­paring 4-phenylpiperidines having calcium overload blocking activity and antidepressant activity, and to novel interme­diates used in that process.
  • Danish patent application no. 5608/87 discloses compounds having the formula (A) wherein R3 is 3,4-methylenedioxyphenyl, aryl or heteroaryl which are optionally substituted with one or more C1 ⁇ 6-alkyl, C1 ⁇ 6-­alkoxy, C3 ⁇ 8-cycloalkyl, C3 ⁇ 5-alkylene or aralkoxy, R1 is straight or branched C4 ⁇ 8-alkyl, C1 ⁇ 8-alkoxy-C4 ⁇ 8-alkyl, C3 ⁇ 7-cycloalkyl, aryloxy-C3 ⁇ 8-alkyl, C4 ⁇ 8-alkenyl, or C3 ⁇ 8-­cycloalkylalkyl, or R1 may also be hydrogen or C1 ⁇ 3-alkyl, when R3 is aryl, which is substituted with two or more of C1 ⁇ 6-alkyl, C1 ⁇ 6-alkoxy, C3 ⁇ 8-cycloalkyl, aralkoxy, or with C
  • These compounds are disclosed as having calcium overload blocking activity, which makes them useful for the treatment of anoxia, ischemia, migraine and epilepsy.
  • Danish patent no. 149843 discloses compounds having the for­mula (B) where R is a C1 ⁇ 4-alkyl- C2 ⁇ 4 alkynyl group, a tetrahydro­naphthyl group or a phenyl group which may be sutstituted 1 or 2 times with halogen or C1 ⁇ 4-alkyl-, C1 ⁇ 4-alkoxy-, C1 ⁇ 4-­alkylthio-, nitro-, C1 ⁇ 4-acylamino- or methylsulphonyl groups or with a methylenedioxy group, R1 is hydrogen, a 2,2,2-tri­fluoroethyl group or a C1 ⁇ 4-alkyl- or C2 ⁇ 4-alkynyl group and X is hydrogen, halogen or a hydroxy-, C1 ⁇ 4-alkyl-, C1 ⁇ 4-­alkoxy-, C1 ⁇ 4-trifluoroalkyl-, methylthio-
  • the compounds of formula (I) are useful in the preparation of compounds of formula (II), (III) and (IV).
  • the compounds of formula (III) are examples of those described in Danish patent application no. 5608/87, and compounds having the formula (IV) are examples of the compounds disclosed in Da­nish patent 149843.
  • N-butyl cinnamoyl amide was prepared in exactly the same way from cinnamoyl chloride and butylamine. M.p. 67.4-­68.1 o C. (4).
  • N-pentyl cinnamoyl amide was prepared in the same way from cinnamoyl chloride and pentylamine. M.p. 68.1-68.7 o C. (5).
  • N-pentyl-2-(3,4-methylenedioxyphenyl)-propenoyl amide was prepared in the same way from 2-(3,4-methylenedioxyphenyl)-­propenoyl chloride and pentylamine.
  • 1-butyl-3-ethoxycarbonyl-4-phenyl-piperidine-2,6-dione was prepared in exactly the same way from sodium diethyl­malonate and (4).
  • the 2,6-dione was an oil.
  • (+-)trans-1-butyl-3-hydroxymethyl-4-phenyl-piperidine was prepared in the same way. M.p. 110 o C. (12).
  • (+-)trans-3-hydroxymethyl-1-pentyl-4-phenyl-piperidine was prepared in the same way. M.p. 115.1 o C. (13).
  • (+-)trans-4-(3,4-methylenedioxyphenyl)-3-hydroxymethyl-­1-pentyl-piperidine was prepared in the same way.
  • (+-)-trans-3-benzenesulfonylmethyl-1-butyl-4-phenyl-pipe­ridine was prepared in the same way. Yielding an oil. (16).
  • (+-)-trans-3-benzenesulfonylmethyl-1-pentyl-4-phenyl-­piperidine was prepared in the same way. Yielding an oil. (17).
  • (+-)trans-3-benzenesulfonylmethyl-4-(3,4-methylenedioxy­phenyl)-1-pentyl-piperidine was prepared in the same way. Yielding an oil. (18).
  • the hydrochloride was prepared from the free amine and conc. HCl in acetone/ether solution. M.p. 139-139.8 o C. (19).
  • (+-)trans-1-butyl-3-(3,4-methylenedioxyphenoxymethyl)-4-­phenyl-piperidine was prepared in the same way. M.p. of the oxalate 115.8 o C. (20).
  • (+-)trans-3-(3,4-methylenedioxyphenoxymethyl)-1-pentyl-4-­phenyl-piperidine was prepared in the same way. M.p. of the hydrochloride 132-133 o C. (21).
  • (+-)trans-4-(3,4-methylenedioxyphenyl)-3-(3,4-methylenedi­oxyphenylmethyl)-1-pentyl-piperidine was prepared in the same way. M.p. of the hydrochloride 156-157 o C. (22).
  • (+-)trans-1-butyl-3-hydroxymethyl-4-phenylpiperidine (4 g) was dissolved in acetone (50 ml) and water (15 ml).
  • (-)-di-p-toluoyl tartaric acid (6.5 g) dissolved in ace­tone (50 ml) was added at 25 o C.
  • the solution was stirred, cooled at 0-5 o C.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Cardiology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel chemical process for pre­paring 4-phenylpiperidines having calcium overload blocking activity and antidepressant activity, and to novel interme­diates used in that process.

Description

  • This invention relates to a novel chemical process for pre­paring 4-phenylpiperidines having calcium overload blocking activity and antidepressant activity, and to novel interme­diates used in that process.
  • Danish patent application no. 5608/87 discloses compounds having the formula (A)
    Figure imgb0001
     wherein
    R³ is 3,4-methylenedioxyphenyl, aryl or heteroaryl which are optionally substituted with one or more C₁₋₆-alkyl, C₁₋₆-­alkoxy, C₃₋₈-cycloalkyl, C₃₋₅-alkylene or aralkoxy,
    R¹ is straight or branched C₄₋₈-alkyl, C₁₋₈-alkoxy-C₄₋₈-alkyl, C₃₋₇-cycloalkyl, aryloxy-C₃₋₈-alkyl, C₄₋₈-alkenyl, or C₃₋₈-­cycloalkylalkyl, or R¹ may also be hydrogen or C₁₋₃-alkyl, when R³ is aryl, which is substituted with two or more of C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, aralkoxy, or with C₃₋₅-alkylene.
    X is hydrogen or halogen, and wherein
    Y is O or S
    and a salt thereof with a pharmaceutically acceptable acid.
  • These compounds are disclosed as having calcium overload blocking activity, which makes them useful for the treatment of anoxia, ischemia, migraine and epilepsy.
  • Danish patent no. 149843 discloses compounds having the for­mula (B)
    Figure imgb0002
     where R is a C₁₋₄-alkyl- C₂₋₄ alkynyl group, a tetrahydro­naphthyl group or a phenyl group which may be sutstituted 1 or 2 times with halogen or C₁₋₄-alkyl-, C₁₋₄-alkoxy-, C₁₋₄-­alkylthio-, nitro-, C₁₋₄-acylamino- or methylsulphonyl groups or with a methylenedioxy group, R¹ is hydrogen, a 2,2,2-tri­fluoroethyl group or a C₁₋₄-alkyl- or C₂₋₄-alkynyl group and X is hydrogen, halogen or a hydroxy-, C₁₋₄-alkyl-, C₁₋₄-­alkoxy-, C₁₋₄-trifluoroalkyl-, methylthio- or benzyloxy group, or optically active forms thereof or salts of the com­pounds with pharmaceutically acceptable acids.
  • These compounds are disclosed as having 5HT uptake inhibiting activity, which makes the compounds useful as antidepressants
  • The compounds of formula (A) are in the Danish patent appli­cation no. 5608/87 prepared by alkylating a compound having the formula (C)
    Figure imgb0003
  • The compounds of Danish patent no. 149843 are made one way or another from an intermediate, having the formula (D)
    Figure imgb0004
  • The methods described in above patent application and in above Danish patent all involve intermediates, which pre­ferably should be avoided. One of these intermediates is arecoline, which is a powerful irritant and another inter­mediate is the compound having the formula (E) 1-methyl-­4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP). This compound is known to be a very powerful neurotoxine and is a strong promotor of irreversible Parkinsonism, (Psychiatry Res., 1 (1979) 249-54; Science, 219 (1983) 979-80).
    Figure imgb0005
  • Therefore there is a need to find another process, avoid­ing this specific compound, for producing the compounds of above Danish patent application no. 5608/87 and Danish patent no. 149843.
  • The novel process provided with the present invention can be illustrated by the following scheme:
    Figure imgb0006
  • The compounds of formula (I) are useful in the preparation of compounds of formula (II), (III) and (IV). The compounds of formula (III) are examples of those described in Danish patent application no. 5608/87, and compounds having the formula (IV) are examples of the compounds disclosed in Da­nish patent 149843.
  • The following examples illustrate the novel process of the present invention, the novel intermediates of the present invention and the utility of the novel intermediates of the present invention.
    • EXAMPLE 1 p-fluoro-cinnamoyl chloride
  • 100 ml SOCl₂ was dropped to 50.5 g (0.3 mol) p-fluorocinnamic acid, the mixture was subsequently heated to reflux for 2 h. The excess of SOCl₂ was evaporated in vacuo. CH₂Cl₂ was added and the reaction mixture was evaporated again. Yield: 56.3 g acid chloride (1).
  • 2-(3,4-methylenedioxyphenyl)-propenoyl chloride was pre­pared in the same way from 2-(3,4-methylenedioxyphenyl)-­propenoic acid and SOCl₂. (2).
    • EXAMPLE 2 N-pentyl-p-fluorocinnamoyl amide
  • 56.3 g (0.3 mol) (1) was dissolved in 400 ml dry toluene. 150 ml triethylamine was added together with 50 ml (0.43 mol) pentylamine under cooling. After 4 h on ice bath the reaction mixture was allowed to warm to room temp., reac­tion time 48 h. The two-phase system was cooled on ice which gave 61.85 g white crystals. The remaining oil was poured into ice and washed with H₂O. The resulting crys­talline compound was filtered off and dried. The first precipitate contained triethylammonium chloride as impuri­ty. Therefore the crystals were washed with water and ex­tracted with ether. The ether layer was dried over MgSO₄ and evaporated. The total amount of amide was 68.5 g. M.p. 79.4-7oC. (3).
  • N-butyl cinnamoyl amide was prepared in exactly the same way from cinnamoyl chloride and butylamine. M.p. 67.4-­68.1oC. (4).
  • N-pentyl cinnamoyl amide was prepared in the same way from cinnamoyl chloride and pentylamine. M.p. 68.1-68.7oC. (5).
  • N-pentyl-2-(3,4-methylenedioxyphenyl)-propenoyl amide was prepared in the same way from 2-(3,4-methylenedioxyphenyl)-­propenoyl chloride and pentylamine. M.p. 96.8-97.4oC. Iden­tified by ¹H-NMR: 0.9-1.0 (t, 3H); 1.3-1.5 (m, 6H); 3.2-­3.5 (q, 2H); 6.0-7.6 (m, 7H). (6).
    • EXAMPLE 3 3-ethoxycarbonyl-4-(4-fluorophenyl)-1-pentyl-piperidine-­2,6-dione
  • 6 g (0.26 mol) sodium was dissolved in 100 ml abs. ethanol. 41.6 g (0.26 mol) diethylmalonate was added with another 200 ml abs. EtOH. 61.9 g (0.20 mol) (3) was added and the mixture refluxed for 4 h. The reaction mixture was very vis­cous. After 2-3 h it was less viscous. The reaction was fol­lowed by means of HPLC.
  • After standing at 60oC over night, dry toluene was added, then the ethanol was distilled off. The reaction mixture was heated for 24 h at 130oC, resulting in precipitation of the product. The precipitate was dissolved in 1N HCl and ex­tracted with ether. The ether layer was dried yielding 74.5 g brown oil. The product was chromatografed on silicagel (eluent CH₂Cl₂/MeOH, 9:1). The product was identified by ¹H-NMR. Yield: 59.8 g yellow oil. ¹H-NMR: 0.8-1.3 (m, 12H); 2.8-4.2 (m, 8H); 6.8-7.5 (m, 4H). (7).
  • 1-butyl-3-ethoxycarbonyl-4-phenyl-piperidine-2,6-dione was prepared in exactly the same way from sodium diethyl­malonate and (4). The 2,6-dione was an oil. ¹H-NMR: 0.8-1.3 (m, 10H); 2.8-4.3 (m, 8H); 7.12 (p, 5H). (8).
  • 3-ethoxycarbonyl-4-phenyl-1-pentyl-piperidine-2,6-dione was prepared in exactly the same way from sodium diethylma­lonate and (5). The 2,6-dione was an oil. ¹H-NMR: 0.9-1.4 (m, 12H); 2.9-4.4 (m, 8H); 7.3 (s, 5H). (9).
  • 3-ethoxycarbonyl-4-(3,4-methylenedioxyphenyl)-1-pentyl-­piperidine-2,6-dione was prepared in the same way from so­dium diethylmalonate and (6). The 2,6-dione which was an oil was identified by ¹H-NMR (10).
    • EXAMPLE 4 (+-)trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-pentyl­piperidine
  • 6 g (0.158 mol) LiAlH₄ was mixed with dry THF. (7) 7,84 g (0,022 mol) dissolved in dry THF was added under N₂. After the addition the reaction mixture was refluxed for 2 h. Sub­sequently H₂O was dropped very cautiously into the solution. The H₂O-phase was extracted with ether. The organic layer was dried over MgSO₄ and evaporated to dryness. Yield: 6.3 g. Recrystallized in ether to give 4 g colourless crystals. M.p. 131-132oC. (11).
  • (+-)trans-1-butyl-3-hydroxymethyl-4-phenyl-piperidine was prepared in the same way. M.p. 110oC. (12).
  • (+-)trans-3-hydroxymethyl-1-pentyl-4-phenyl-piperidine was prepared in the same way. M.p. 115.1oC. (13).
  • (+-)trans-4-(3,4-methylenedioxyphenyl)-3-hydroxymethyl-­1-pentyl-piperidine was prepared in the same way. M.p. 126-127oC. ¹H-NMR: 0.9-1.2 (t, 3H); 1.3-2.5 (m, 14H); 3.0-­3.5 (m, 5H); 5.8 (s, 2H); 6.6 (s, 3H). (14).
    • EXAMPLE 5 (+-)trans-3-benzenesulfonylmethyl-4-(4-fluorophenyl)-1-­pentyl-piperidine
  • 10 g (0.036 mol) (11) was dissolved in toluene and MIBC. 10.1 g (0.057 mol) benzenesulfonyl chloride and 8 ml 50% NaOH was added. Reaction time 4 h at room temp. 4N NaOH was added and the organic phase was separated. The water phase was washed with ether. The organic layer was washed with 4N NaOH, then dried and evaporated, resulting in 7 g as an oil. The iden­tity was confirmed by ¹H-NMR. Yield: 85%. (15).
  • (+-)-trans-3-benzenesulfonylmethyl-1-butyl-4-phenyl-pipe­ridine was prepared in the same way. Yielding an oil. (16).
  • (+-)-trans-3-benzenesulfonylmethyl-1-pentyl-4-phenyl-­piperidine was prepared in the same way. Yielding an oil. (17).
  • (+-)trans-3-benzenesulfonylmethyl-4-(3,4-methylenedioxy­phenyl)-1-pentyl-piperidine was prepared in the same way. Yielding an oil. (18).
    • EXAMPLE 6 (+-)trans-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxy­methyl)-1-pentyl-piperidine
  • 7 g (0.017 mol) (15) was dissolved in toluene and MIBC. 2.4 g (0.017 mol) sesamol and 4 ml 50% NaOH was added. The reac­tion mixture was refluxed for 5 h. The organic layer was washed with 4N NaOH, dried over MgSO₄ and evaporated. HPLC showed that 84% of the resulting oil was VI. The oil was dissolved in acetone and 1 eq of oxalic acid was added. Re­crystallization of the resulting precipitate gave 3 g of the title compound as the oxalate. This oxalate gave 2.6 g free amine as an oil, by extraction with 4N NaOH/ether.
  • The hydrochloride was prepared from the free amine and conc. HCl in acetone/ether solution. M.p. 139-139.8oC. (19).
  • (+-)trans-1-butyl-3-(3,4-methylenedioxyphenoxymethyl)-4-­phenyl-piperidine was prepared in the same way. M.p. of the oxalate 115.8oC. (20).
  • (+-)trans-3-(3,4-methylenedioxyphenoxymethyl)-1-pentyl-4-­phenyl-piperidine was prepared in the same way. M.p. of the hydrochloride 132-133oC. (21).
  • (+-)trans-4-(3,4-methylenedioxyphenyl)-3-(3,4-methylenedi­oxyphenylmethyl)-1-pentyl-piperidine was prepared in the same way. M.p. of the hydrochloride 156-157oC. (22).
    • EXAMPLE 7 (+-)trans-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxy­methyl)-piperidine
  • 1.48 g (0.0037 mol) (19) was dissolved in dry 1,2-dichloro­ethane. 0,8 g (0,0056 mol) 1-chloro-ethylchloroformate was added slowly under N₂ and with rapid stirring at 0oC. The temperature was kept at 0oC for 15 min. Then the reaction mixture was allowed to warm to room temp., and subsequently refluxed for 30 min. Then the volume was reduced to one third, by evaporation. Methanol was added and the mixture refluxed for 1.5 h. The reaction mixture was evaporated in vacuo, giving an oil. The oil was chromatographed on a sili­ca column with CH₂Cl₂/methanol (9:1) as eluent, giving 0.25 g of the starting material and 1.05 g of the hydrochloride of the title compound. M.p. 98-98.5oC. (23).
    • EXAMPLE 8 (-)trans-1-butyl-3-hydroxymethyl-4-phenyl-piperidine-(-)-­di-p-toluoyl tartrate
  • (+-)trans-1-butyl-3-hydroxymethyl-4-phenylpiperidine (4 g) was dissolved in acetone (50 ml) and water (15 ml). (-)-di-p-toluoyl tartaric acid (6.5 g) dissolved in ace­tone (50 ml) was added at 25oC. The solution was stirred, cooled at 0-5oC. The crystals were filtered off, washed with acetone and dried. Yield 3.5 g, m.p. 177-178oC, [α] 20 D
    Figure imgb0007
     = -89.4o (c = 2% in methanol). (24).
  • (-)trans-3-hydroxymethyl-1-pentyl-4-phenyl-piperidine-(-)-­di-p-toluoyl tartrate was prepared in the same way. M.p. 165-166oC, [α] 20 D
    Figure imgb0008
     = -86.6o (c = 2% in methanol). (25).
    • EXAMPLE 9 (-)trans-1-butyl-3-hydroxymethyl-4-phenyl-piperidine
  • (-)trans-1-butyl-3-hydroxymethyl-4-phenyl-piperidine-(-)-­di-p-toluyl tartrate (2 g) was dispensed in water (10 ml), sodium hydroxide 4N (5 ml) and toluene (50 ml) was added. The toluene extract was dried over potassium carbonate, filtered, evaporated at reduced pressure and crystallized from acetone. Yield 0.7 g, m.p. 97-99oC, [α] 20 D
    Figure imgb0009
     -27.9o (c = 5% in methanol). (26).
  • (-)trans-3-hydroxymethyl-1-pentyl-4-phenyl-piperidine was prepared in the same way. M.p. 84-86oC, [α] 20 D
    Figure imgb0010
    = -24.2o (c = 5% in methanol). (27).

Claims (2)

1. A compound having the formula
Figure imgb0011
 wherein R is alkyl;
R¹ is C₄-C₈-alkyl, C₁₋₈-alkoxy-C₄₋₈-alkyl, C₃₋₇-cycloalkyl, aryloxy-C₃₋₈-alkyl, C₄₋₈ alkenyl, or C₃₋₈-cycloalkylalkyl; X is hydrogen or halogen.
2. A process for the preparation of a compound having the formula
Figure imgb0012
 wherein R¹ and X have the meanings set forth in claim 1 CHARACTERIZED in reducing a compound having the formula
Figure imgb0013
 wherein R¹, X and R have the meanings set forth above.
EP89122827A 1988-12-22 1989-12-11 Reduction of piperidine-dion-derivatives and intermediates Withdrawn EP0374675A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK716088A DK716088D0 (en) 1988-12-22 1988-12-22 REDUCTION OF PIPERIDIN-DION DERIVATIVES AND INTERMEDIATE
DK7160/88 1988-12-22

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EP0374675A2 true EP0374675A2 (en) 1990-06-27

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JP (1) JPH02225468A (en)
AU (1) AU4692889A (en)
CA (1) CA2005355A1 (en)
DK (1) DK716088D0 (en)
FI (1) FI896096A0 (en)
IL (1) IL92682A0 (en)
NO (1) NO895195L (en)
PT (1) PT92716A (en)
ZA (1) ZA899778B (en)

Cited By (11)

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WO1993022284A1 (en) * 1992-05-06 1993-11-11 Smithkline Beecham Plc Process for stereospecific hydrolysis of piperidinedione derivatives
WO1994021609A1 (en) * 1993-03-13 1994-09-29 Smithkline Beecham P.L.C. Process for preparing acryl-piperidine carbinols
WO1997044320A1 (en) * 1996-05-24 1997-11-27 Fmc Corporation Improved processes for the reduction of imide ester functionality
ES2121685A1 (en) * 1996-04-10 1998-12-01 Vita Invest Sa Process for obtaining (+/-)-trans-4-(4-fluorophenyl)-3- hydroxymethyl-1-methylpiperidine
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
US6197960B1 (en) 1996-04-15 2001-03-06 Asahi Glass Company Ltd. Process for producing piperidinecarbinols
AT407528B (en) * 1995-02-06 2001-04-25 Smithkline Beecham Plc NEW FORMS OF PAROXETINE HYDROCHLORIDE ANHYDRATE
US6444190B2 (en) 1995-08-03 2002-09-03 Fmc Corporation Reduction compositions and processes for making the same
US6444822B1 (en) * 1999-08-02 2002-09-03 Chemi S.P.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivative
EP1242378A1 (en) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Novel processes

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
IL98757A (en) * 1990-07-18 1997-01-10 Novo Nordisk As Piperidine derivatives their preparation and pharmaceutical compositions containing them

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993022284A1 (en) * 1992-05-06 1993-11-11 Smithkline Beecham Plc Process for stereospecific hydrolysis of piperidinedione derivatives
WO1994021609A1 (en) * 1993-03-13 1994-09-29 Smithkline Beecham P.L.C. Process for preparing acryl-piperidine carbinols
AP452A (en) * 1993-03-13 1996-01-19 Smithkline Beecham Plc "Diborane reduction of certain aryl piperidines".
AU682497B2 (en) * 1993-03-13 1997-10-09 Smithkline Beecham Plc Process for preparing acryl-piperidine carbinols
US5681962A (en) * 1993-03-13 1997-10-28 Smithkline Beecham Plc Process for preparing aryl-piperidine carbinols
CN1041918C (en) * 1993-03-13 1999-02-03 史密丝克莱恩·比彻姆有限公司 Process for preparing acryl-piperidine carbinols
CN1055470C (en) * 1993-03-13 2000-08-16 史密丝克莱恩比彻姆有限公司 Paroxetine and process for preparing medical salts thereof
AT407528B (en) * 1995-02-06 2001-04-25 Smithkline Beecham Plc NEW FORMS OF PAROXETINE HYDROCHLORIDE ANHYDRATE
US6444190B2 (en) 1995-08-03 2002-09-03 Fmc Corporation Reduction compositions and processes for making the same
ES2121685A1 (en) * 1996-04-10 1998-12-01 Vita Invest Sa Process for obtaining (+/-)-trans-4-(4-fluorophenyl)-3- hydroxymethyl-1-methylpiperidine
US6197960B1 (en) 1996-04-15 2001-03-06 Asahi Glass Company Ltd. Process for producing piperidinecarbinols
US6590102B1 (en) 1996-04-15 2003-07-08 Asahi Glass Company Ltd. Process for producing piperidinecarbinols
US6476228B1 (en) 1996-04-15 2002-11-05 Asahi Glass Company Ltd. Process for producing piperidinecarbinols
US5936090A (en) * 1996-05-24 1999-08-10 Fmc Corporation Processes for the reduction of imide ester functionality
WO1997044320A1 (en) * 1996-05-24 1997-11-27 Fmc Corporation Improved processes for the reduction of imide ester functionality
US5874447A (en) * 1997-06-10 1999-02-23 Synthon B. V. 4-Phenylpiperidine compounds for treating depression
US7598271B1 (en) 1997-06-10 2009-10-06 Noven Therapeutics, Llc Crystalline paroxetine methane sulfonate
US6900327B2 (en) 1997-06-10 2005-05-31 Synthon Bct Technologies, Llc 4-phenylpiperidine compounds
US6063927A (en) * 1998-07-02 2000-05-16 Smithkline Beecham Plc Paroxetine derivatives
US6444822B1 (en) * 1999-08-02 2002-09-03 Chemi S.P.A. Process for the preparation of 3-substituted 4-phenyl-piperidine derivative
EP1242378A4 (en) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Novel processes
EP1242378A1 (en) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Novel processes

Also Published As

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NO895195L (en) 1990-06-25
NO895195D0 (en) 1989-12-21
AU4692889A (en) 1990-06-28
IL92682A0 (en) 1990-09-17
PT92716A (en) 1990-06-29
DK716088D0 (en) 1988-12-22
FI896096A0 (en) 1989-12-19
JPH02225468A (en) 1990-09-07
CA2005355A1 (en) 1990-06-22
ZA899778B (en) 1990-09-26

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